Generally, chiral C2-bis(oxazolines) are known to serve as successful ligands in several catalytic processes, including Diels-Alder, aldol, aziridination, allylic alkylation and cyclopropanation reactions. Complex catalysts consisting of conjugate between chiral 2,2′-cyclopropylidene-bis-oxazoles and magnesium triflate in combination with amine provides addition of ketoesters or malonates to nitroolefins with excellent enantioselectivity (e.g., Ji J., et al., J. Am. Chem. Soc., 1999, 121, 10215, and Barnes D. M., et al., J. Am. Chem. Soc., 2002, 124, 13097). Nichols P., et al. in WO2004096764 patent application discloses a method of preparing ring compounds with chiral centers in the presence of a catalyst complex comprising bis(oxazolines) as a ligand.
At the same time, application of this methods for large-scale production of asymmetric organic compounds is problematic from economical point of view, mainly due to the employment of expensive chiral bis(oxazolines) in technological process as disposable material. Previous attempts to develop a method for recovery of that valuable catalyst in such reactions include immobilization of the bis(oxazoline) catalyst on organic and inorganic polymers, ion-pairing with an anionic support and covalent attachment to silica. Examples of regeneration of insoluble polymer-bound bis(oxazolines) were described, e.g., polystyrene-bound, as showed by P. Salvadori et al., Tetrahedron: Asymmetry, 2004, 15, 3233, and grafted on ArgoGel, as shown by C. Moberg et al., Tetrahedron: Asymmetry, 2001, 12, 1475. A number of sources describe the use of ionic liquids and anionic solids to obtain recoverable catalysts for reactions promoted by cationic chiral bis(oxazoline) complexes (e.g. J. A. Mayoral et al., Green Chem., 2004, 6, 93 and D. L. Davies et al., Tetrahedron: Asymmetry, 2004, 15, 77). Additionally, J. A. Mayoral et al. presented immobilization of bis(oxazolines) by functionalization of the central methylene bridge with polymerizable organic groups and subsequent polymerization (Org. Lett., 2000, 2, 3905) and grafting bis(oxazolines) functionalized with two allyl or vinylbenzyl groups onto mercaptopropylsilica (J. Org. Chem., 2001, 66 (26), 8893).
One example is known for 4-naphthyl-substituted bis(oxazoline) ligand to be recovered from reaction mixture by a simple filtration due to its low solubility in polar solvents (G. Desimoni et al., Tetrahedron, 1998, 51, 15721).
Summarizing the entire above-mentioned prior art, except of the very last one, it should be underlined that immobilization of chiral bis(oxazoline) catalysts has substantial disadvantages. Usually, the type of immobilization modifies the catalytic performance and, in particular, the enantioselectivity. In most cases immobilization requires chemical modification of the ligand with changes in its activity and selectivity. In some cases polymer was reported to inhibit the entire reaction. Enantioselectivity issues were discussed also in case of ionic liquids, where crucial role plays the stability of the catalyst complex (when the complex is not so stable, the equilibrium between the complexed and free form of the metal may lead to the presence of nonchiral sites, with the consequent reduction in enantioselectivity), purity of the ionic liquid, its dryness and synthetic method used or preparation of the ionic liquid. Moreover, some of recovery procedures of the immobilized catalyst are likely not to be translated to an industrial scale due to particular specific steps (e.g. use of saturated solution of KCN in DMSO as by C. Moberg et al., Tetrahedron: Asymmetry, 2001, 12, 1475).
The above-mentioned recovery of 4-naphthyl-substituted bis(oxazoline) ligand from reaction mixture by filtration due to its low solubility in polar solvents is a standalone example which characterizes that particular ligand and cannot be considered as a general procedure.
Thus, no universal method, easily scaled to industrial application, was describes so far, providing selective isolation of bis(oxazolines) per se from homogeneous solutions and their multiple usage for catalytic purposes.
Obviously, development of easy and effective method for isolation of chiral 2,2′-cyclopropylidene-bis(oxazolines) from the homogeneous reaction mixture for a multiple usage is highly desirable and potentially of a significant positive economical effect. Effective isolation of chiral 2,2′-cyclopropylidene-bis(oxazolines) from reaction mixture and its repeated re-use in synthetic procedure could significantly improve both technological and economical characteristics of the large-scale production of desired asymmetric products.
The present invention overcomes disadvantages of the recovery methods known up to date and provides for a simple and effective method of regeneration of chiral 2,2′-cyclopropylidene-bis(oxazolines) from reaction mixtures, as described further, without loss in catalytic quality.